Technical Field
This disclosure is related to pharmaceutical formulations comprising artificial retinoids, in particular, to stable formulations and dosage formulations suitable for visual chromophore replacement therapy.
Description of the Related Art
Visual perception results from a biological conversion of light energy into electrical signaling by retinal photoreceptors in the eye, a process called phototransduction. The phototransduction process is initiated by visual pigments, including the chromophore 11-cis-retinal bound to apoprotein G protein-coupled receptor opsins to form rhodopsin (Palczewski K. G protein-coupled receptor rhodopsin. Annual review of biochemistry 2006; 75:743-767). The chromophore absorbs photons, which triggers photoisomerization of the chromophore into its trans form and leads to signal transduction cascades (Palczewski K. supra; Ridge K D et al. Visual rhodopsin sees the light: structure and mechanism of G protein signaling, J Biol Chem 2007; 282:9297-9301). The isomerized chromophore, all-trans-retinal, is then reduced to all-trans-retinol, transported to the retinal pigmented epithelium (RPE), and converted to fatty acid all-trans-retinyl esters by lecithin:retinol acyltransferase (LRAT). Finally, regeneration of 11-cis-retinal from the fatty acid all-trans-retinyl esters completes this retinoid (visual) cycle (see, e.g., U.S. Published Application Nos. 2004/0242704, 2006/028182, 2006/0221208).
Regeneration of 11-cis-retinal is critical for maintaining vision (Travis G H, et al. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. Annu Rev Pharmacol Toxicol 2007; 47:469-512). Defects in 11-cis-retinal production are associated with a number of inherited degenerative retinopathies (Gu S M, et al. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nature genetics 1997; 17:194-197). Two examples are Leber congenital amaurosis (LCA), a childhood-onset retinal disease causing severe visual impairment; and retinitis pigmentosa (RP), another retinopathy with a more variable age of onset.
LCA is an inherited, severe, and currently incurable retinal degeneration that is a leading cause of blindness during childhood. At or soon after birth, LCA patients characteristically exhibit severe visual impairment evidenced by wandering nystagmus, amaurotic pupils, a pigmentary retinopathy with toss of cone and rod sensitivity, absent or greatly attenuated eiectroretinogram (ERG) responses and a ˜100 folds decrease in cone flicker amplitude (Perrault I, et al. Leber congenital amaurosis, Mol Genet Metab 1999; 68:200-208; Fazzi E, et al. Leber's congenital amaurosis: an update. Eur J Paediatr Neurol 2003; 7:13-22; Fazzi E, et al. Response to pain in a group of healthy term newborns: behavioral and physiological aspects. Functional neurology 1996; 11:35-43).
RPE65, a 65 kDa protein specific to and abundant in the RPE that catalyses the isomerization of fatty acid all-trans-retinyl esters to 11-cis-retinol, is generally considered as the retinoid isomerase involved in the regeneration of 11-cis-retinal (Hamel C P. et al. Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro. J Biol Chem 1993; 268:15751-15757; Jin M, et al. Rpe65 is the retinoid isomerase in bovine retinal pigment epithelium. Cell 2005; 122:449-459; Moiseyev G, et al. RPE65 is the isomerohydrolase in the retinoid visual cycle. Proceedings of the National Academy of Sciences of the United States of America 2005; 102:12413-12418; Redmond T M. et al. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proceedings of the National Academy of Sciences of the United States of America 2005; 102:13658-13663). Mutations in the RPE65 gene account for up to 16% of LCA cases and 2% of autosomal recessive RP cases (Gu S M, supra; Marlhens F, et al. Mutations in RPE65 cause Leber's congenital amaurosis. Nature genetics 1997; 17:139-141; Morimura H, et al. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis Proceedings of the National Academy of Sciences of the United States of America 1998; 95:3088-3093; Thompson D A, et al. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Investigative ophthalmology & visual science 2000; 41:4293-4299; Lorenz B, et al. Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Investigative ophthalmology & visual science 2000; 41:2735-2742). Spontaneous or engineered deletions of Rpe65 in mice and dogs result in 11-cis-retinal deficiency, an early-onset and slowly progressive retinal degeneration with dramatically reduced electroretinogram (ERG) responses and typical LCA pathology accompanied by accumulation of fatty acid all-trans-retinyl esters in the RPE (Redmond T M, et al. Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle. Nature genetics 1998; 20:344-351; Pang J J, et al. Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). Molecular vision 2005; 11:152-162; Wrigstad A, et al. Ultra structural changes of the retina and the retinal pigment epithelium in Briard dogs with hereditary congenital night blindness and partial day blindness. Experimental eye research 1992; 55:805-818; Acland G M, et al. Gene therapy restores vision in a canine model of childhood blindness. Nature genetics 2001; 28:92-95; Imanishi Y, et al. Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye. The Journal of cell biology 2004; 164:373-383).
Several possible therapies for treating LCA are being investigated. RPE65 gene augmentation therapy and retinal prostheses have shown preliminary encouraging signs of visual rescue in early-stage clinical evaluations (Bainbridge J W, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. The New England journal of medicine 2008; 358:2231-2239; Maguire A M, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. The New England journal of medicine 2008; 358:2240-2248; Yanai D, et al. Visual performance using a retinal prosthesis in three subjects with retinitis pigmentosa. American journal of ophthalmology 2007; 143:820-827).
Recently, visual chromophobe replacement therapy with 9-cis-retinal has been proposed as a novel pharmacological approach to bypass the defective retinoid cycle (Van Hooser J P, et al. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. Proceedings of the National Academy of Sciences of the United States of America 2000; 97:8623-8628; Van Hooser J P. et al. Recovery of visual functions in a mouse model of Leber congenital amaurosis. J Biol Chem 2002; 277:19173-19182; Aleman T S, et al. Impairment of the transient pupillary light reflex in Rpe65(+/−) mice and humans with leber congenital amaurosis. Investigative ophthalmology & visual science 2004; 45:1259-1271; Batten M L, et al. Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse Model of Leber Congenital Amaurosis. PLoS Med 2005; 2:e333). 9-cis-retinal binds to opsin to form the rod cell pigment, iso-rhodopsin, which initiates phototransduction similarly to rhodopsin. It has been shown that oral administration of 9-cis-retinal or its precursors have regenerated opsin as iso-rhodopsin in the eyes, improved retinal function as assessed by ERG responses, and ameliorated the pupillary light reflex in Rpe65 and Lrat knockout mice, which are two genetic models of LCA. There is a need to further develop synthetic 9-cis-retinols in orally-, gastric-, locally- (such as intravitreal), or intravenously-administered formulations for the treatment of various forms of inherited retinal degeneration caused by defects in the retinoid cycle.